Attenuation of hypertrophy in chondrogenically differentiating human mesenchymal stem cells via treatment with a retinoic acid receptor inverse agonist

Die körpereigene Fähigkeit zur Regeneration von elenkknorpel nach traumatischer oder degenerativer Schädigung ist stark eingeschränkt. Mesenchymale Stammzellen (MSCs) sind eine vielversprechende Quelle zur Regeneration von esenchymalem Gewebe wie etwa hyalinem Knorpel. MSCs haben das Potential zukünftig autologe Chondrozyten in der Therapie von Knorpeldefekten zu ersetzen. Es besteht die Chance, dass die pluripotenten Zellen die embryonale Entwicklung von Gelenkknorpelzellen während der Skelettformation nachvollziehen können. Jedoch exprimieren in vitro chondrogen differenzierten MSCs hypertrophe Marker wie Kollagen X und atrixmetalloproteinase 13 (MMP13). Dies zeigt, dass die Chondrogenese der MSCs nicht auf einer für Gelenkknorpelzellen üblichen Entwicklungsstufe endet, sondern spontan weiterläuft hin zu einem hypertrophen Stadium, wie es für die Chondrozyten der Wachstumsfuge während der enchondralen Ossifikation typisch ist. Da Hypertrophie jedoch langfristig in Apoptose und Ossifikation mündet, schränkt dieser Umstand den Einsatz von MSCs in tissue engineering von Gelenkknorpel maßgeblich ein. In der Skelettentwicklung übt der Retinsäure - Rezeptor (RAR) – Signalweg einen wichtigen Einfluss auf die Entwicklung von mesenchymalen Vorläuferzellen aus. Während Retinoide die Chondrogenese hemmen und die Hypertrophie in der Wachstumsfuge fördern, scheint die Unterdrückung der RAR-Wirkung für frühe chondrogene Differenzierungsstufen notwendig zu sein. Daher haben wir die Hypothese aufgestellt, dass die Behandlung von chondrogen differenzierenden Chondrozyten mit dem inversen RAR-Agonisten BMS 204,493 die Hypertrophie hemmen kann. Um diese Hypothese zu überprüfen haben wir die Wirkung von BMS auf humane MSCs auf histologischer, genetischer sowie Protein-Ebene untersucht. Hypertrophie wurde in chondrogen vordifferenzierten MSCs durch den Entzug von transforming growth factor β (TGFβ) und Dexamethason sowie durch den Einfluss von bone morphogenic protein 4 (BMP4) induziert. Die Behandlung mit BMS bewirkte nach Einleitung der Hypertrophie eine Hemmung der hypertrophen Differenzierung der hMSCs, deutlich zu erkennen an der geringeren Zellgröße, ALP-Aktivität und Kollagen X - Genexpression sowie - Produktion. Die Wirkung von BMS war abhängig vom Zeitpunkt der Applikation und am stärksten ausgeprägt bei Anwendung in der frühen Phase der Differenzierung. Die Möglichkeit die Entwicklung von MSCs durch die II Hemmung des RAR-Signalwegs durch BMS zu modifizieren dürfte für die Produktion von stabilem Gewebe zur Regeneration von Gelenkknorpel hilfreich sein

Patients with Small Acetabular Cartilage Defects Caused by Femoroacetabular Impingement Do Not Benefit from Microfracture

Objective: According to current recommendations, large cartilage defects of the hip over 2 cm2 are suggested to undergo autologous chondrocyte transplantation (ACT), while small defects should be treated with microfracture. We investigated if patients with small chondral defects of the hip joint (≤100 mm2 ) actually benefit from microfracture. Design: In this retrospective multicenter cohort study 40 patients with focal acetabular cartilage defects smaller than 100 mm2 and of ICRS grade ≥2 caused by femoroacetabular impingement were included. Twenty-six unrandomized patients underwent microfracture besides treatment of the underlying pathology; in 14 patients cartilage lesions were left untreated during arthroscopy. Over a mean follow-up of 28.8 months patient-reported outcome was determined using the iHOT33 (international hip outcome tool) and the VAS (visual analog scale) for pain. Results: The untreated group showed a statistically significant improvement of the iHOT33 after 12 (p = 0.005), 24 (p = 0.019), and 36 months (p = 0.002) compared to the preoperative score, whereas iHOT33 in the microfracture group did not reveal statistically significant changes over time. There was no significant difference between both groups on any time point. Regarding pain both groups did not show a significant improvement over time in the VAS. Conclusion: The subjective outcome of patients with small cartilage defects of the hip (≤100 mm2 ) improves 12 months after arthroscopic FAIS surgery without any cartilage treatment. However, no improvement could be seen after microfracture. Therefore, a reserved surgical treatment for small cartilage defects of the hip under preservation of the subchondral bone is recommended especially if a simultaneous impingement correction is performed

Treatment of Fracture-Related Infection after Pelvic Fracture

Background: The management of pelvic fractures is a significant challenge. Surgical site infection can result in the need for revision surgery, cause functional impairment, and lead to a prolonged length of stay and increased treatment costs. Although reports on fracture-related infection (FRI) after pelvic fracture fixation are sparsely reported in the literature, it is a serious complication. This study analysed patients with FRIs after pelvic fracture regarding patient characteristics, treatment strategies, and an evaluation of risk factors for FRI. Methods: In this retrospective single-centre study, FRI was diagnosed based on clinical symptoms of infection and a positive culture of a bacterial infection. Depending on the severity and acuteness of the infection, osseous stabilization was restored either via implant retention (stable implant, no osteolysis), exchange (loose implant or bony defect), or external fixation (recurrence of infection after prior implant retaining revision). Healing of infection was defined as no sign of recurring infection upon clinical, radiological, and laboratory examination in the last follow-up visit. Results: The FRI rate in our patient population was 7.5% (24/316). In 8/24 patients, the FRI occurred within the first three weeks after initial surgery (early) and 16/24 presented with a late onset of symptoms of FRI. A strategy of debridement, antibiotics, and implant retention (DAIR) was successful in 9/24 patients with FRI after pelvic fracture. A total of 10 patients required an exchange of osteo-synthetic implants, whereof three were exchanged to an external fixator. In five patients, we removed the implant because the fracture had already consolidated at the time of revision for infection. A total of 17/24 patients had a poly-microbial infection after a pelvic fracture and 3/24 patients died from post-traumatic multi-organ failure within the first 6 months after trauma. There were no cases of persistent infection within the remaining 21 patients. Conclusions: Although poly-microbial infection is common in FRI after pelvic fracture, the recurrence rate of infection is relatively low. A complex pelvic trauma with significant soft tissue injury is a risk factor for recurrent infection and multiple revisions. A strategy of DAIR can be successful in patients with a stable implant. In cases with recurrent infection or an unstable fracture site, the exchange of implants should be considered

No effect of dislocation status at arrival in emergency department on outcome of knee joint dislocations

Purpose Knee dislocation is a rare but severe injury of the lower extremities. The aim of this study was to report on the epidemiology, diagnostics and treatment of such injuries and to identify negative predictors of clinical outcomes. Methods This retrospective analysis included all knee dislocations treated at a Level I Trauma Centre in Germany between 2009 and 2021. Medical records were categorised, collected and analysed in a standardised manner. A follow-up visit 1 year after the injury focused on limitations in knee mobility. Results A total of 120 knee dislocations were included in the study. 29.3% of patients presented to the emergency department with a dislocated joint, and 17.5% (n = 21) had a neurovascular lesion. At follow-up 12 months after the injury, 65.8% of the patients reported limitations in the range of motion, and 11.7% (n = 14) reported severe limitations in daily activities. Site infections due to surgery occurred in 3.3% of patients. Increased body weight (r = 0.294; p < 0.001 and r = 0.259; p = 0.004), an increased body mass index above 25 kg/m2 (body mass index, r = 0.296; p < 0.001 and r = 0.264; p = 0.004) and deficits in peripheral perfusion as well as sensory and motor function (r = 0.231; p = 0.040 and r = −0.192; p = 0.036) were found to be negative predictive factors for clinical outcome. For posttraumatic neurovascular injury, lack of peripheral perfusion, insufficient sensory and motor function (r = −0.683; p < 0.0001), as well as a higher Schenck grade (r = 0.320; p = 0.037), were identified as independent risk factors. The status of dislocation at the site of the accident and on arrival at the emergency department had no impact on the outcome or neurovascular injury. Conclusion Knee dislocation is a rare injury with a high rate of severe complications such as neurovascular lesions. In particular, the initial status of neurovascular structures and injury classification showed a relevant negative correlation with the posttraumatic status of nerves and vessels. In particular, patients with these characteristics need close monitoring to prevent negative long-term consequences

The Loop Tenodesis Procedure—From Biomechanics to First Clinical Results

(1) Introduction: Several surgical therapy options for the treatment of pathologies of the long biceps tendon (LHB) have been established. However, tenotomy, as well as established tenodesis techniques, has disadvantages, such as cosmetic deformities, functional impairments and residual shoulder pain. This study presents the first clinical and structural results of the recently introduced loop tenodesis procedure for the LHB, developed to overcome these issues. (2) Methods: 37 patients (11 women, 26 men, mean age 52 years), who underwent loop tenodesis of the LHB were examined six months after surgery. For the clinical evaluation the Constant score, as well as the LHB score, were used, complemented by elbow flexion and supination strength measurements. The integrity of the tenodesis construct was evaluated indirectly by sonographic detection of the LHB in the bicipital groove. (3) Results: Both, the overall Constant score as well as the LHB score showed significant improvements six months postoperatively, as compared to the preoperative value. Fourteen patients (38%) presented an examiner-dependent upper arm deformity, although only five patients (13%) reported subjective cosmetic deformities. Both, flexion and supination strength were preserved compared to the preoperative level. In 35 patients (95%), the tenodesis in the bicipital groove was proofed sonographically. (4) Conclusion: The loop tenodesis of the LHB provides good-to-excellent overall clinical results after a short-term follow-up of six month. The incidence of cosmetic deformities was inferior compared to conventional therapy options (tenotomy and anchor tenodesis)

Is the Tendon-to-Groove Ratio Associated with Elevated Risk for LHB Tendon Disorders?—A New Approach of Preoperative MR-Graphic Analysis for Targeted Diagnosis of Tendinopathy of the Long Head of Biceps

Background: Pathologies of the long head of the biceps (LHB) tendon are a common cause of anterior shoulder pain. While the influence of the anatomical morphology of the intertubercular groove (ITG) on the development of LHB tendon instability has been investigated with ambiguous results, the relationship of the LHB to ITG anatomy has not yet been considered in this context. The objective of this study was to reliably extract the tendon-to-groove ratio from MRI scans of symptomatic patients and examine its potential influence on the occurrence of certain causes for LHB-associated symptoms. Methods: In this retrospective study, preoperative MRI scans of 35 patients (mean age of 46 ± 14 years) presenting with anterior shoulder pain and clinical indications of LHB tendinopathy were analyzed in transversal planes. Long and short diameters of the LHB tendon and ITG were measured, cross-sectional areas of the LHB tendon and ITG were calculated from these measurements, and the ratio of cross-sectional areas (LHB/ITG) was introduced. All measurements were repeated independently by three investigators and inter-rater reliability was assessed using intraclass correlation coefficient (ICC). Thereafter, tendon-to-groove ratios were compared in patients with and without intraoperative signs of LHB tendon instability. Results: All patients exhibited intraoperative signs of LHB tendinitis, with additional findings including pulley lesions and SLAP lesions. Analysis revealed variations in the dimensions of the LHB tendon and ITG cross sections, with the tendon-to-groove ratio decreasing from 37% at the pulley to 31% at the deepest point of the sulcus. Very good inter-rater reliability was observed for all measurements. The tendon-to-groove ratio did not significantly differ (p > 0.05) in patients with or without pulley lesions or SLAP lesions. Conclusions: Our study introduced the novel parameter of the tendon-to-groove ratio of cross-sectional areas as a reproducible parameter for the description of local anatomy in the field of targeted diagnosis of LHB tendon disorders. While our findings do not yet support the predictive value of the tendon-to-groove ratio, they underscore the importance of further research with larger cohorts and control groups to validate these observations

Anterior Column Reconstruction of Destructive Vertebral Osteomyelitis at the Thoracolumbar Spine with an Expandable Vertebral Body Replacement Implant: A Retrospective, Monocentric Radiological Cohort Analysis of 24 Cases

Background: Vertebral osteomyelitis (VO) often necessitates surgical intervention due to bone loss-induced spinal instability. Anterior column reconstruction, utilizing expandable vertebral body replacement (VBR) implants, is a recognized approach to restore stability and prevent neurological compromise. Despite various techniques, clinical evidence regarding the safety and efficacy of these implants in VO remains limited. Methods: A retrospective cohort analysis, spanning 2000 to 2020, was conducted on 24 destructive VO cases at a Level 1 orthopedic trauma center. Diagnosis relied on clinical, radiological, and microbiological criteria. Patient demographics, clinical presentation, surgical interventions, and radiological outcomes were assessed. Results: The study included 24 patients (62.5% male; mean age 65.6 ± 35.0 years), with 58% having healthcare-associated infections (HAVO). The mean radiological follow-up was 137.2 ± 161.7 weeks. Surgical intervention significantly improved the bi-segmental kyphotic endplate angle (BKA) postoperatively (mean −1.4° ± 13.6°). However, a noticeable loss of correction was observed over time. The study reported a mortality rate of 1/24. Conclusions: Anterior column reconstruction using expandable VBR effectively improved local spinal alignment in destructive VO. However, the study underscores the necessity for prolonged follow-up and continuous research to refine surgical techniques and postoperative care. Addressing long-term complications and refining surgical approaches will be pivotal as the field progresses

Benefit of second-line therapy for advanced esophageal squamous cell carcinoma: a tri-center propensity score analysis

BACKGROUND: The level of evidence for palliative second-line therapy in advanced esophageal squamous cell carcinoma (aESCC) is limited. This is the first study that reports efficacy data comparing second-line therapy + active symptom control (ASC) versus ASC alone in aESCC. METHODS: We conducted a tri-center retrospective cohort study (n = 166) including patients with aESCC who had experienced disease progression on palliative first-line therapy. A propensity score model using inverse probability of treatment weighting (IPTW) was implemented for comparative efficacy analysis of overall survival (OS) in patients with second-line + ASC (n = 92, 55%) versus ASC alone (n = 74, 45%). RESULTS: The most frequent second-line regimens used were docetaxel (36%) and paclitaxel (18%). In unadjusted primary endpoint analysis, second-line + ASC was associated with significantly longer OS compared with ASC alone [hazard ratio (HR) = 0.49, 95% confidence interval (CI): 0.35–0.69, p < 0.0001]. However, patients in the second-line + ASC group were characterized by more favorable baseline features including a better Eastern Cooperative Oncology Group (ECOG) performance status, a longer first-line treatment duration and lower C-reactive protein levels. After rigorous adjusting for baseline confounders by re-weighting the data with the IPTW the favorable association between second-line and longer OS weakened but prevailed. The median OS was 6.1 months in the second-line + ASC group and 3.2 months in the ASC group, respectively (IPTW-adjusted HR = 0.40, 95% CI: 0.24–0.69, p = 0.001). Importantly, the benefit of second-line was consistent across several clinical subgroups, including patients with ECOG performance status ⩾1 and age ⩾65 years. The most common grade 3 or 4 adverse events associated with palliative second-line therapy were hematological toxicities. CONCLUSION: This real-world study supports the concept that systemic second-line therapy prolongs survival in patients with aESCC

Proximal Humerus Fractures in the Elderly U.S. Population: A Cross-Sectional Study of Treatment Trends and Comparison of Complication Rates after Joint Replacement, Open Reduction and Internal Fixation, and Non-Surgical Management

Proximal humerus fracture (PHF) treatment remains challenging. Multiple therapy options exist, and the optimal choice of management has been increasingly discussed in the literature. The aim of this study was to (1) analyze trends in the propensity of proximal humerus fracture treatments and (2) compare complication rates after joint replacement, surgical repair, and non-surgical treatment in terms of mechanical complications, union failure, and infection rates. In this cross-sectional study, patients aged 65 years or older with proximal humerus fractures occurring between 1 January 2009 and 31 December 2019 were identified from Medicare physician service claims records. The Kaplan–Meier method with the Fine and Gray adjustment was used to calculate the cumulative incidence rates for malunion/nonunion, infection, and mechanical complications for the following treatment categories: shoulder arthroplasty, open reduction and internal fixation (ORIF), and non-surgical treatment, respectively. Semiparametric Cox regression was performed incorporating 23 demographic, clinical, and socioeconomic covariates to determine risk factors. Between 2009 through 2019, conservative procedures decreased by 0.9%. ORIF procedures decreased from 9.51% (95% CI: 8.7–10.4) to 6.95% (95% CI: 6.2–7.7), whereas shoulder arthroplasties rose from 1.99% (95% CI: 1.6–2.4), to 5.45% (95% CI: 4.8–6.2). PHFs managed through ORIF were associated with higher union failure rates compared to conservatively treated fractures (HR = 1.31, 95% CI: 1.15–1.5, p < 0.001). The risk of developing an infection was increased after joint replacement compared to ORIF (2.66% vs. 1.09%, HR = 2.09, 95% CI: 1.46–2.98, p < 0.001). Mechanical complications were more common after joint replacement (6.37% vs. 4.85%, HR = 1.66, 95% CI: 1.32–2.09, p < 0.001). Complication rates differed significantly across treatment modalities. This should be considered when choosing a management procedure. Vulnerable elderly patient cohorts could be identified, and the optimization of modifiable risk factors might lead to a decrease of complication rates in both surgically and non-surgically treated patients

Diaphragmatic Injuries among Severely Injured Patients (ISS ≥ 16)—An Indicator of Injury Pattern and Severity of Abdominal Trauma

Background and Objectives: Abdominal trauma among severely injured patients with an injury severity score (ISS) of 16 and above can lead to potentially life-threatening injuries that might need immediate surgical intervention. Traumatic injuries to the diaphragm (TID) are a challenging condition often accompanied by other injuries in the thoracoabdominal region. Materials and Methods: We retrospectively analyzed the occurrence and clinical course of TID among severely injured patients treated at our center between 2008 and 2019 and compared them to other groups of severely injured patients without TID. Results: Thirty-five patients with TID and a median ISS of 41 were treated in the period mentioned above. They were predominantly middle-aged men and mostly victims of blunt trauma as a consequence of motor vehicle accidents. A total of 70.6% had left-sided TID, and in 69.6%, the size of defect was larger than 10 cm. The diagnosis was made with computed tomography (CT) in 68.6% of the cases, while in 25.8%, it was made intraoperatively or delayed by a false-negative initial CT scan, and in 5.7%, an intraoperative diagnosis was made without preoperative CT imaging. Surgical repair was mostly conducted via laparotomy, performing a direct closure with continuous suture. A comparison to 191 patients that required laparotomy for abdominal injuries other than TID revealed significantly higher rates of concomitant injuries to several abdominal organs among patients suffering from TID. Compared to all other severely injured patients treated in the same period (n = 1377), patients suffering from TID had a significantly higher median ISS and a longer mean duration of hospital stay. Conclusions: Our findings show that TID can be seen as an indicator of particularly severe thoracoabdominal trauma that requires increased attention from the treatment team so as not to miss relevant concomitant injuries that require immediate intervention